This application is the National Phase of International Application PCT/GB00/01173 filed Mar. 27, 2000 which designated the U.S. and that International Application was published under PCT Article 21(2) in English.
This invention relates to the preparation of carvone (5-isopropenyl-2-methyl-2-cyclohexen-1-one) and in particular to the conversion of carvoxime (5-isopropenyl-2-methyl-2-cyclohexen-l-one oxime) to carvone.
L-Carvone (5(R)-isopropenyl-2-methyl-2-cyclohexen-1-one) is widely used as an odorant or flavouring component for tooth paste or powder, chewing gum, mouthwashes etc. In these dental applications, it is important the carvone has a high purity and, in particular, it is important that hydroxy compounds, such as xcex1-terpineol, a common by-product of carvone synthesis, are present at a low level. These materials often cannot be separated from carvone by distillation and a laborious, costly and effluent-intensive bisulphite extraction and wash is generally needed to remove the contaminants. An alternative method which is suitable for separating by-products such as xcex1-terpineol is disclosed in U.S. Pat. No. 5,302,759. The process described in this patent utilises the reaction between an organometallic compound and an alcohol to bring about a separation of an alcohol from a ketone. Unfortunately, this purification process is not economical when the amount of hydroxy compounds present in the carvone is relatively high.
In one process for preparing carvone, carvoxime is hydrolysed by transoximation under acidic conditions with sulphuric acid and acetone. While the hydrolysis affords reasonable yields of carvone, substantial amounts of xcex1-terpineol, formed from limonene, and hydroxycarvone are formed. Moreover, stoichiometric amounts of acetoxime, a suspected carcinogen, are formed as side products and a large amount of sulphate effluent is produced. Hence, the process, although practical, carries a substantial environmental burden. Furthermore, the amount of xcex1-terpineol and hydroxycarvone generated from the process means that the purification method disclosed in U.S. Pat. No. 5,302,759 cannot be applied economically and hence a bisulphite treatment is needed to purify the resulting carvone in order to produce dental quality product. This results in a further environmental burden.
In the search for an environmentally friendly carvone production process, one of the important objectives is elimination of the formation of the toxic acetoxime which is produced in the above-mentioned process, as shown in the following scheme: 
One solution is a reductive deoximation of carvoxime which is described in Japanese Patent Application JP 50 071 648 in which metallic iron in aqueous carboxylic acid is used for the reduction. An ammonium salt is the side product of this process, and the production of acetoxirne is therefore eliminated. However, a stoichiometric amount of iron is used and stoichiometric amount of iron salt/iron oxide is formed as a side product.
Catalytic hydrogenation is a well-known and useful industrial technique that can be applied on a manufacturing scale and which uses a cheap reducing agent, namely hydrogen. The problem with using hydrogenation in the reductive deoximation of carvoxime is that the reagent may not be selective. Thus, the two olefin functional groups can be saturated readily to produce dihydrocarvones and/or tetrahydrocarvones.
Hydrogenation has been used to synthesise olefins from alkynes, the hydrogenation being better known as Lindlar""s hydrogenation (Lindlar, H.; Dubuis, R. Organic Synthesis Coll. Vol. V, 1973, p.880). Lindlar""s hydrogenation normally uses a palladium on calcium carbonate or palladium on barium sulphate catalyst that is selectively poisoned by, for example, a lead salt or quinoline.
It has now been found that the formation of hydroxy compounds such as a-terpineol during the synthesis of carvone can be minimised by using a hydrogenation process to convert carvoxime to carvone. Surprisingly, hydrogenation catalysts, such as Lindlar""s catalyst, have been found to efficiently convert carvoxime to carvone.
According to the invention, there is provided a process for the preparation of carvone comprising hydrogenating carvoxime in the presence of a selectively poisoned catalyst.
The process is illustrates by the following reaction scheme. 
The reaction product, carvone, can exist as optical isomers. The more useful and preferred, isomer is L-carvone although the process is equally suitable for producing D-carvone.
The carvone produced using this process contains a relatively small amount of hydroxy compounds, particularly a-terpineol, and therefore the process of U.S. Pat. No. 5,302,759 can be economically employed to purify the product. Therefore, in a preferred embodiment, the process of the invention further comprises a purification of the reaction product carvone by treating the crude carvone product with an organometallic compound M(X)n wherein M is a polyvalent metal, n is the valence of M and X denotes an inorganic or organic atom or group.
The starting material, carvoxime, in the process of the invention, can be prepared by any suitable method. Typically, limonene (d-) is reacted with nitrosyl chloride to give a chloronitrosylated product which, on dehydrochlorination and tautomerisation, yields carvoxime.
This crude carvoxime product is then converted to carvone using the process of the invention. Alternatively, the crude carvoxime may be purified before use. Carvoxirne is hydrogenated by heating the carvoxime in the presence of a hydrogen source and a selectively poisoned catalyst.
The preferred reaction temperature is in the range 80xc2x0 C. to 180xc2x0 C. and, more preferably in the range 120xc2x0 C. to 155xc2x0 C.
A suitable, and preferred, hydrogen source for use herein is hydrogen gas. In this case, the reaction is preferably carried out at a pressure above atmospheric pressure, typically at a pressure in the range 1.0 to 10.0 MPa, and, more preferably, in the range 4.0 to 6.0 MPa.
Alternatively, the hydrogen source can be any compound which is a hydrogen donor. Suitable examples include formic acid; formate salts such as sodium formate; secondary alcohols such as isopropanol; cyclohexene; cyclohexadienes; tetralin; teipinolenes; limonene; or other unsaturated cycloalkanes. Preferably, the hydrogen donor is formic acid which is buffered by a salt. Suitable salts for use herein include, but are not limited to sodium acetate, bicarbonates, carboxylates, hydrogen phosphate, dihydrogen phosphate or ammonium salts. Preferably, the salt is sodium acetate.
When the hydrogen source is a hydrogen donor, the reaction can be carried out at atmospheric pressure, and so may be performed using ordinary apparatus.
In accordance with the invention, the reaction is carried out in the presence of a poisoned catalyst. By xe2x80x9cpoisoned catalystxe2x80x9d is meant a catalyst which is active in promoting conversion of the oxime group to a ketone group but does not hydrogenate the carbon-carbon double bonds in the carvoxirne molecule significantly. Typically the catalyst is a supported metal catalyst, especially a noble metal catalyst and effective catalysts include, but are not limited to, metals, such as palladium, supported on a material, such as barium sulphate or alumina, which have been poisoned by mixing with a catalyst modifier such as a lead compound or quinoline. A particularly preferred catalyst is palladium on barium sulphate poisoned by red lead oxide (Pb3O4).
Generally, the catalyst will be present in an amount in the range 0. 1% to 10.0% by weight of carvoxime and preferably in an amount in the range 3.0% to 6.0% by weight of carvoxime.
The hydrogenation of carvoxirne produces ammonia as a by product and it is preferable to add an acid to the reaction mixture to neutralise the ammonia produced. Many acids can be used, including organic and inorganic acids but preferred acids include carboxylic acids such as acetic acid or formic acid.
The hydrogenation of carvoxime using the process in accordance with the invention has been found to introduce very little, if any, hydroxy compounds into the carvone, although the earlier stages of the usual synthesis from limonene do produce some hydroxy compounds.
In a preferred embodiment of the process defined herein, carvone, prepared according to the process of the present invention is purified according to the process described in U.S. Pat. No. 5,302,759, the teachings of which are hereby incorporated by reference, wherein the crude carvone is treated with an organometallic compound of formula M(X)n, as hereinbefore defined. M is a polyvalent metal atom, preferably selected from titanium, aluminium or boron. n is the valence of the metal, i.e. l equals 4 for titanium and 3 for aluminium or boron. X is an alkoxy group, typically having 1 to 10 carbon atoms and preferably 1 to 4 carbon atoms. Particularly preferred alkoxy groups for use herein are methoxy, ethoxy, propoxy or butoxy.
Preferably, when the organometallic compound added is an alkoxide, there will be a by-product alcohol (e.g. isopropanol from tetraisopropoxytitanium) which is sufficiently volatile to be removed from the carvone before the carvone is distilled.
The amount of organometallic compound used will depend principally upon the amount of hydroxy compound present in the crude carvone product. Usually, the amount of M(X)n added to the crude carvone is sufficient to produce a molar ratio of M(X)n to hydroxy compound in the range 0.5:1 to 1.5:1 and preferably in the range 0.75:1 to 1:1.
The carvone produced according to the preferred process of the invention is particularly useful for dental flavourings and generally contains low levels of undesirable impurities.